1 Structural and Functional Alterations in the Brain Gray Matter

Structural and functional alterations in the brain gray matter among first-degree relatives of schizophrenia patients: a multimodal meta-analysis of fMRI and VBM studies Running title: Familial risk for schizophrenia and alterations in the brain Aino I. L. Saarinen, PhD1,2,3,*, Sanna Huhtaniska, MD, PhD4, Juho Pudas, MB3, Lassi Björnholm, MD3, Tuomas Jukuri, MD, PhD3, Jussi Tohka, MD, PhD5, Niklas Granö, PhD6, Jennifer H. Barnett, PhD7,8, Vesa Kiviniemi, MD, PhD9,10, Juha Veijola, MD, PhD3,10,11, Mirka Hintsanen, PhD1, Johannes Lieslehto, MD, PhD 12 1 Research Unit of Psychology, University of Oulu, Finland 2 Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Finland 3 Research Unit of Clinical Neuroscience, Department of Psychiatry, University of Oulu, Finland 4 Center for Life Course Health Research, University of Oulu, Finland 5 A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland 6 Helsinki University Hospital, Department of Adolescent Psychiatry, Finland 7 Cambridge Cognition, Cambridge, UK 8 Department of Psychiatry, University of Cambridge, Cambridge, UK 9 Department of Diagnostic Radiology, Oulu University Hospital, Oulu, Finland 10 Department of Psychiatry, Oulu University Hospital, Oulu, Finland 11 Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland 12 Section for Neurodiagnostic Applications, Department of Psychiatry, Ludwig Maximilian University, Nussbaumstrasse 7, 80336 Munich, Bavaria, * Corresponding author: Aino Saarinen. Department of Psychology and Logopedics, Faculty of Medicine, Haartmaninkatu 3, P.O. Box 21, 00014 University of Helsinki, Finland. E-mail: [email protected], Tel.: +35844 307 1204. 1 Abstract Objective: Schizophrenia has one of the highest heritability estimates in psychiatry, but the genetically- based underlying neuropathology has mainly remained unclear. We conducted a multimodal coordinate- based meta-analysis (CBMA) to investigate brain structural and functional alterations in individuals with high familial risk for schizophrenia, i.e. in first-degree relatives of schizophrenia patients (FRs). Methods: We conducted a systematic literature search from two electronic databases to find studies that examined differences between FRs and healthy controls using whole-brain functional magnetic resonance imaging (fMRI) or voxel-based morphometry (VBM). A CBMA of 30 fMRI (754 FRs; 959 controls) and 11 VBM (885 FRs; 775 controls) datasets were conducted using the anisotropic effect-size version of signed differential mapping. Further, we conducted separate meta-analyses about functional alterations in different cognitive tasks: social cognition, executive functioning, working memory, and inhibitory control. Results: When compared to healthy controls, FRs showed higher fMRI activation in the right frontal gyrus during cognitive tasks. In VBM studies, there were no differences in grey matter density between FRs and healthy controls. Furthermore, multi-modal meta-analysis obtained no differences between FRs and healthy controls. Finally, by utilizing the BrainMap database, we showed that the brain region which showed functional alterations in FRs (i) overlapped only slightly with the brain regions that were affected in the meta-analysis of schizophrenia patients and (ii) correlated positively with the brain regions that exhibited increased activity during cognitive tasks in healthy individuals. Conclusions: Based on this meta-analysis, FRs may exhibit only minor functional alterations in the brain during cognitive tasks, and the alterations are much more restricted and only slightly overlapping with the regions that are affected in schizophrenia patients. The familial risk did not relate to structural alterations in the grey matter. Keywords: Schizophrenia; Psychosis; Genetic risk; Familial risk; Brain structure; Brain activity 2 1 Introduction The heritability of schizophrenia and psychotic disorders may be as high as 80% (Sullivan et al., 2003), but the genetically-based underlying neuropathology is mostly unknown. First-degree relatives of schizophrenia patients (FRs) compose a particular risk group since their lifetime morbidity risk for schizophrenia is increased ten-fold to 10% (Gottesman et al., 2010; Lichtenstein et al., 2006). Consequently, when evaluating an individual’s risk for schizophrenia, the familial risk is among the most important factors (Mäki et al., 2005). Cognitive impairment is very common in prodromal schizophrenia (Cornblatt et al., 2004; Lencz et al., 2006). Furthermore, large cognitive deficits are present prior to illness onset and represent vulnerability markers for the onset of the disorder (Carrión et al., 2018). Along with this, cognitive impairment is also included as a diagnostic criterion for schizophrenia in the DSM-V classification. Overall, cognitive functioning is shown to be more severely impaired in genetic than clinical high-risk populations (Seidman et al., 2010). The most affected cognitive abilities are executive functioning, such as working memory and inhibitory control (Snitz et al., 2005), and social cognition (Cornblatt et al., 2003; Hans et al., 2010). Consequently, cognitive impairment is a crucial element when aiming to identify predictors for the onset of schizophrenia. Previous meta-analyses suggest that relatives of schizophrenia patients have increased activity in the right-side parietal, temporal, and frontal regions (Cooper et al., 2014; Scognamiglio et al., 2014; Zhang et al., 2016). Findings on brain regions with decreased activity in FRs have been inconclusive, with findings in the thalamus, cerebellum, cingulate, or frontal lobes (Cooper et al., 2014; Scognamiglio et al., 2014; Zhang et al., 2016; Niu et al., 2017). Regarding structural alterations, FRs seem to have decreased gray matter in the insula and frontal regions, even though the findings have varied somewhat (Cooper et al., 2014; Niu et al., 2017; Boos et al., 2007). Multimodal meta-analyses in FRs have been inconclusive (Cooper et al., 2014; Niu et al., 2017). 3 An updated meta-analysis on this topic is very much needed for several reasons. Firstly, a growing number of original studies have been conducted on this topic during recent years, so a higher number of participants are available for a meta-analysis. Secondly, previous meta-analyses have not investigated functional alterations in FRs separately in different cognitive tasks. This might be important since there is evidence that different cognitive abilities may be selectively impaired among individuals at risk for schizophrenia (Cornblatt et al., 2003; Hans et al., 2000). Thirdly, there is a possibility that alterations in genetic high-risk individuals are located in overlapping regions but are more subtle than in schizophrenia patients. However, this has remained uninvestigated in the previous meta-analyses. Finally, previous meta- analyses have not examined if the functional alterations during cognitive tasks in FRs are located in the brain regions that exhibit increased activity during cognitive tasks in healthy individuals. This is a crucial question since there is evidence about compensating mechanisms in the brain among individuals at risk for psychosis (Cooper et al., 2014; Fusar-Poli et al., 2010; Pulkkinen et al., 2015). For example, it is possible that before any psychotic symptomatology has emerged, FRs can compensate for mild cognitive impairments by activating more extensive brain networks (i.e. different/additional brain regions than in healthy individuals) during a cognitive task. Our first aim was to conduct a multimodal meta-analysis in order to investigate the functional and structural alterations in first-degree relatives of schizophrenia patients. We included peer-reviewed functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM) studies with whole- brain scanning. Our second aim was to investigate whether brain regions with structural or functional alterations in FRs overlap with the regions (i) that are affected in schizophrenia patients or (ii) that exhibit increased activity during cognitive tasks in healthy individuals. For this purpose, we utilized the publically available meta-analysis database BrainMap. We did not set a-priori hypotheses in this study. 2 Methods 2.1 Search strategies 4 The MOOSE (Meta-analyses Of Observational Studies in Epidemiology) Checklist was followed throughout the meta-analysis (https://www.elsevier.com/__data/promis_misc/ISSM_MOOSE_Checklist.pdf). The fulfilled form of the MOOSE Checklist can be found in Supplementary Table 1. A systematic literature search was carried out between August and November 2018 using the electronic databases of PubMed and Web of Science. For fMRI studies, we used the following search terms: “schizophrenia” AND (“genetic risk” OR “familial risk” OR “parental risk” OR “relatives” OR “twins” OR “offspring” OR “siblings”) AND (“fMRI” OR “functional MRI” OR “BOLD”). For VBM studies, the search terms included: “schizophrenia” AND (“genetic risk” OR “familial risk” OR “parental risk” OR “relatives” OR “twins” OR “offspring” OR “siblings”) AND (“VBM” OR “gray matter” OR “gray matter" OR "voxel-based morphometry"). There were no restrictions regarding language, publication date, or publication status, and the search was directed to all fields. After removing duplicates, all identified studies were screened based on the title and abstract and defined as eligible/ineligible for the meta-analysis. In

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